PROJECT SUMMARY/ABSTRACT The coronavirus SARS-CoV-2 (Covid-19 or 2019-nCoV) emerged in Wuhan, China, in late 2019 and then rapidly spread worldwide. It causes severe acute respiratory syndrome (SARS) with substantial morbidity and mortality. Little is yet known whether the CNS is involved, but other coronaviruses are known to invade the brain. There is as yet, however, no published data on the presence or neuropathological consequences of CNS SARS-CoV-2 in infected humans. This project aims to fill this important knowledge gap. The Arizona ADCC became the NIA's first statewide AD Center in 2001. Since then, it has established Clinical and Neuropathology Cores that are world-class resources of longitudinally assessed individuals, and, together with an extraordinary ancillary Brain and Body Donation Program, annually contribute on average 80 autopsied subjects. In this supplemental application we propose to conduct important studies probing the extent and consequences of SARS-CoV-2 CNS infection in an estimated 100 or more subjects coming to autopsy over an 18 month period spanning the global pandemic. The project is supported by an extremely strong, multidisciplinary team. Specific Aim 1 will determine the prevalence of CNS infection with SARS-CoV-2 in consecutive autopsies, using postmortem nasal swab, postmortem blood serology and assay of multiple brain regions for SARS-CoV-2 RNA. Specific Aim 2 will assess the gene expression effects of brain regional SARS-CoV-2 infection using RNAseq transcriptomics. Deconvolution analysis will infer gene expression changes separately for neurons, microglia, astrocytes, oligodendrocytes and endothelial cells. Hypothetical gene expression effects would include those typical for inflammatory responses, cell death and demyelination. Additionally, this analysis will put SARS-CoV-2 findings into perspective vs other microbial or viral presence as detected by their specific transcripts, reflecting past pathogen exposure history. Specific Aim 3 will determine the neuropathological correlates of the findings from Specific Aims 1 and 2, by surveying the brain for typical viral-associated histopathology including meningitis, encephalitis, microglial nodules, perivascular mononuclear cell cuffing and demyelination, and by determining with immunohistochemistry and in-situ hybridization whether specific cell types are infected. These findings may yield critical clues useful for devising diagnostic and therapeutic strategies for possible neurological manifestations of SARS-CoV-2 and the planned studies provide an unprecedented opportunity to survey the prevalence and extent of brain invasion by a novel pathogen during a worldwide pandemic.